Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination

Tracy J. Yuen, Kory R. Johnson, Veronique E. Miron, Chao Zhao, Jacqueline Quandt, Marie C. Harrisingh, Matthew Swire, Anna Williams, Henry F. McFarland, Robin J M Franklin, Charles Ffrench-Constant

Research output: Contribution to journalArticle

Abstract

The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.

Original languageEnglish (US)
Pages (from-to)1035-1047
Number of pages13
JournalBrain
Volume136
Issue number4
DOIs
StatePublished - 2013
Externally publishedYes

Fingerprint

Endothelin-2
Endothelin B Receptors
Demyelinating Diseases
Central Nervous System
Zymosan
Oligodendroglia
Myelin Sheath
Innate Immunity
Multiple Sclerosis
Retina
Macrophage Activation
Microarray Analysis
Regeneration
Cytokines
Therapeutics
Endothelin B Receptor Antagonists

Keywords

  • endothelin
  • inflammation
  • multiple sclerosis
  • oligodendrocytes
  • regeneration
  • remyelination

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Yuen, T. J., Johnson, K. R., Miron, V. E., Zhao, C., Quandt, J., Harrisingh, M. C., ... Ffrench-Constant, C. (2013). Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. Brain, 136(4), 1035-1047. https://doi.org/10.1093/brain/awt024

Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. / Yuen, Tracy J.; Johnson, Kory R.; Miron, Veronique E.; Zhao, Chao; Quandt, Jacqueline; Harrisingh, Marie C.; Swire, Matthew; Williams, Anna; McFarland, Henry F.; Franklin, Robin J M; Ffrench-Constant, Charles.

In: Brain, Vol. 136, No. 4, 2013, p. 1035-1047.

Research output: Contribution to journalArticle

Yuen, TJ, Johnson, KR, Miron, VE, Zhao, C, Quandt, J, Harrisingh, MC, Swire, M, Williams, A, McFarland, HF, Franklin, RJM & Ffrench-Constant, C 2013, 'Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination', Brain, vol. 136, no. 4, pp. 1035-1047. https://doi.org/10.1093/brain/awt024
Yuen, Tracy J. ; Johnson, Kory R. ; Miron, Veronique E. ; Zhao, Chao ; Quandt, Jacqueline ; Harrisingh, Marie C. ; Swire, Matthew ; Williams, Anna ; McFarland, Henry F. ; Franklin, Robin J M ; Ffrench-Constant, Charles. / Identification of endothelin 2 as an inflammatory factor that promotes central nervous system remyelination. In: Brain. 2013 ; Vol. 136, No. 4. pp. 1035-1047.
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abstract = "The development of new regenerative therapies for multiple sclerosis is hindered by the lack of potential targets for enhancing remyelination. The study of naturally regenerative processes such as the innate immune response represents a powerful approach for target discovery to solve this problem. By 'mining' these processes using transcriptional profiling we can identify candidate factors that can then be tested individually in clinically-relevant models of demyelination and remyelination. Here, therefore, we have examined a previously described in vivo model of the innate immune response in which zymosan-induced macrophage activation in the retina promotes myelin sheath formation by oligodendrocytes generated from transplanted precursor cells. While this model is not itself clinically relevant, it does provide a logical starting point for this study as factors that promote myelination must be present. Microarray analysis of zymosan-treated retinae identified several cytokines (CXCL13, endothelin 2, CCL20 and CXCL2) to be significantly upregulated. When tested in a cerebellar slice culture model, CXCL13 and endothelin 2 promoted myelination and endothelin 2 also promoted remyelination. In studies to identify the receptor responsible for this regenerative effect of endothelin 2, analysis of both remyelination following experimental demyelination and of different stages of multiple sclerosis lesions in human post-mortem tissue revealed high levels of endothelin receptor type B in oligodendrocyte lineage cells. Confirming a role for this receptor in remyelination, small molecule agonists and antagonists of endothelin receptor type B administered in slice cultures promoted and inhibited remyelination, respectively. Antagonists of endothelin receptor type B also inhibited remyelination of experimentally-generated demyelination in vivo. Our work therefore identifies endothelin 2 and the endothelin receptor type B as a regenerative pathway and suggests that endothelin receptor type B agonists represent a promising therapeutic approach to promote myelin regeneration.",
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